The large majority of cancer-caused deaths (>90%) do not result from the primary tumor, but from the spread of cancer cells from their location of origin to other sites of the body - a process known as metastasis. Despite this understanding, most cancer treatments are designed to target the primary tumor, not metastatic lesions. A major limitation in developing targeted anti-metastatic therapies is a lack of understanding of the biological drivers of this process in cancer cells. It has been demonstrated by a number of recent studies that epigenetic marks identifying gene enhancer elements across a cell's genome are highly predictive of cell-type-specific patterns of gene expression and are therefore highly informative of cellular behavior. One such study applying epigenetic enhancer profiling to the study of cancer has revealed unprecedented insight into the molecular alterations that drive tumor formation. In the proposed studies, this approach will be applied to investigate epigenetic alterations driving the process of metastasis in the most common primary tumor of bone, osteosarcoma. This is a highly aggressive solid tumor that commonly affects adolescents, often resulting in death from metastatic progression to the lung. Unfortunately, long-term outcomes for these patients have not improved for over 30 years. Through application of this epigenetic approach, this project seeks to gain insight into the molecular underpinnings of osteosarcoma metastasis with the goal of identifying metastatic drivers that may serve as suitable therapeutic targets as well as molecular signatures predictive of metastatic risk in osteosarcoma patients. Successful completion of these studies not only offer the potential to improve outcomes for osteosarcoma patients, but also to gain insight into the process of metastasis, in general, that may inform the study of other types of cancer.